Urinary peptides in heart failure: a link to molecular pathophysiology
Tianlin He, Michaela Mischak, Andrew L Clark, Ross T Campbell, Christian Delles, Javier Díez, Gerasimos Filipatos, Alexandre Mebazaa, John J V McMurray, Arantxa González, Julia Raad, Rafael Stroggilos, Helle S Bosselmann, Archie Campbell, Shona Kerr, Colette E Jackson, Jane A Cannon, Morten Schou, Nicolas Girerd, Patrick Rossignol, Alex McConnachie, Kasper Rossing, Joost P Schanstra, Faiez Zannad, Antonia Vlahou, William Mullen, Vera Jankowski, Harald Mischak, Zhenyu Zhang, Jan A Staessen, Agnieszka Latosinska
Aims: Heart failure (HF) is a major public health concern worldwide. The diversity of HF makes it challenging to decipher the underlying complex pathological processes using single biomarkers. We examined the association between urinary peptides and HF with reduced (HFrEF), mid-range (HFmrEF) and preserved (HFpEF) ejection fraction, defined based on European Society of Cardiology guidelines, and the links between these peptide biomarkers and molecular pathophysiology.
Methods and results: Analysable data from 5,608 participants were available in the Human Urinary Proteome database. The urinary peptide profiles from participants diagnosed with HFrEF, HFmrEF, HFpEF and controls matched for sex, age, estimated glomerular filtration rate, systolic and diastolic blood pressure, diabetes and hypertension were compared applying the Mann Whitney test, followed by correction for multiple testing.
Unsupervised learning algorithms were applied to investigate groups of similar urinary profiles. 577 urinary peptides significantly associated with HF were sequenced, 447 of which (77%) were collagen fragments. In silico analysis suggested that urinary biomarker abnormalities in HF principally reflect changes in collagen turnover and immune response, both associated with fibrosis. Unsupervised clustering separated study participants into two clusters, with 83% of non-HF controls allocated to cluster 1, while 65% of patients with HF were allocated to cluster 2 (p<0.0001). No separation based on HF subtype was detectable.
Conclusions: HF, irrespective of ejection fraction subtype, was associated with differences in abundance of urinary peptides reflecting collagen turnover and inflammation. These peptides should be studied as tools in early detection, prognostication, and prediction of therapeutic response.